The average American visits a doctor 4 times a year(Elation Health). There could be multiple reasons for this - maybe routine check-ups, or you're just feeling sick. When our health isn't too bright, we can always count on our heroic doctors to come save us. But what if doctors couldn't solve the problems presented to them? This could've been a stark reality for us without the lifesaving invention of antibiotics. More specifically, in 1928, Alexander Fleming, A Scottish physicist, discovered penicillin, which was a natural toxin secreted by bacteria to compete with other bacteria for resources. This was life-changing for everyone around the world, because now, a simple cut could be easily cured with minimal side-effects without having to worry about dying to a deadly bacterial infection. But, everyone(or everything) gets their 15 minutes of being famous, and soon, antibiotics could die out because of a new nightmare: Multi-drug resistant bacteria. Even though this soon could essentially render our antibiotics useless, a chosen hero known as the bacteriophage could save us. But in order to use this effective weapon against the bloodthirsty bacteria, the public must urge more efforts to research around this lifesaving tool so that we can save more lives.
In 2019, a six-week old Dutch girl named Rosa had acquired a simple viral respiratory (lung) infection. The parents, Aart and Lina, were not worried at all, as they had experience in this field because they were doctors. This simple infection soon turned into a nightmare for them, as it had been discovered that Rosa had been infected with a strain of multi-drug resistant bacteria called Klebsiella Pneumoniae. Her mother, Lina, recalls, "For me it was a real concern. We were completely shocked because doctors had been treating her for nearly a week thinking that the problem was being solved. However, in reality, the treatment was not effective at all." Lina was shocked and scared mainly because her daughter was being colonized by superbugs, which were resistant to almost all antibiotics, meaning that the bacteria would be hard to fight off against if they used antibiotics. Soon, after multiple surgeries and treatments, the bacterial infection was quelled, and life could go back to normal. But furthermore, it was discovered that Rosa had her hip dislocated because of all the commotion the infection had caused her. Lina urgently stresses, "It wasn't just a two-months-in-a-hospital story. These were three long years of surgical interventions, rehabilitation of her uncertainty about her future."(European Antibiotic Awareness Day) This occurrence of antimicrobial resistance is not rare either. Besides Rosa, many people have gone through this complicated recovery path to fight off MDR bacteria. For instance, a 2019 WHO report on antimicrobial resistance details, "Antimicrobial resistance is responsible for 1.27 million deaths worldwide, with approximately 80% of these deaths linked to six bacterial species, including Staphylococcus Aureus and Pseudomonas Aeruginosa. If current trends persist, by 2050, the number of deaths caused by multi-drug resistant bacteria could surpass that caused by cancer..." Undoubtedly, the prevalence of multi-drug resistant bacteria today is increasing at a rapid rate, so it is an issue to be taken seriously. Multi-drug resistant organisms, defined by the WHO as a phenomenon that "occurs when bacteria, viruses, fungi, and parasites no longer respond to antimicrobial medicines," are increasing in rates never seen before. More importantly, the WHO also writes, "the misuse and overuse of antimicrobials in humans, animals, and plants are the main drivers in the development of drug-resistant pathogens." In simpler terms, bacterial resistance to drugs is something that us humans can speed up. We do it all the time when we use antibiotics for a harmless infection that our immune system could've fought off by itself, and this overuse of antibiotics helps bacteria to evolve via natural selection and become resistant to a fortitude of antibiotics. And as the epidemic of drug-resistant bacteria rages on, newer and effective antibiotics to combat them are too expensive and take too much time to develop, leading to more deaths globally.
This problem poses a new opportunity for the practice of phage therapy to re-emerge. The University of San Diego's School of Medicine describes phages, or more formally known as bacteriophages, as, "viruses that solely kill and selectively target bacteria. They are the most common biological entities in nature, and have been shown to effectively fight and destroy multi-drug resistant bacteria." Bacteriophages are shown to specifically target bacteria, and so they can be described as viruses for the bacteria. There has been no evidence to prove that phages can directly kill human cells (Volkers, 2022). In fact, bacteriophages are so specialized that they can only infect a certain species of bacteria, or as Laura Kasman stipulates, "... bacteriophages are species-specific about their hosts, and usually only infect a single bacterial species or even specific strains within a species." Because of this reality of new multi-drug resistant bacteria, phages are going to be tried as a treatment, because they are much more specific and more. Clearly, bacteriophages are completely harmless to us humans and can effectively save us from the new reality we might experience soon: multi-drug resistant bacteria. To truly understand the effect of these germ-killers, we need to analyze their impact in a historical context.
The history of bacteriophages has been shrouded with mystery, but some reports suggest phages were discovered as early as 1896, when George Hankin, an English bacteriologist living in colonial India, first documented these microscopic beasts. The National Library of Medicine presents, "[Hankin] observed in the waters of the Ganges and the Jumna river [phages] ... responsible for limiting the spread of cholera epidemics." The Russian bacteriologist Gamaleya soon followed this breakthrough by discovering and observing these bacteriophages. The research of phages wasn't pursued until Félix d'Herelle, French-Canadian microbiologist at the Institut Pasteur in Paris, 'officially' documented it. After d'Herelle had conducted many experiments regarding the subject, phage therapy largely died out in the west. As the American Society for Microbiology resolves, "... phage therapy eventually fell out of favor in the West for several reasons. For one, scientists were skeptical about how well it worked. Improper phage storage or purification likely played a role... Scientists also didn't understand that phages were highly specific for the bacteria they targeted." The Society adds, "[World War II] prompted scientists in western Europe and the U.S. to avoid phage therapy, given its close ties to the former Soviet Union. The discovery of penicillin was the final nail in phage therapy's coffin—the advent of antibiotics revolutionized how bacterial infections were treated and became the gold standard in much of the world."(National Library of Medicine, 2001) The main reasons phage therapy isn't as prevalent as it was expected to be is because scientists were skeptical about them and phage therapy was closely tied to the Soviet Union, a country that the West didn't want to be associated with. Ultimately, antibiotics drove the extinction of phage therapy because at first they were cheaper to produce. But soon, this will not be the most efficient way to combat these pathogens. Kurzgesagt, a non-profit YouTube channel whose primary aim is to educate and inform the public, accurately compares, "Antibiotics are like carpet-bombing, killing everything, even the good bacteria in our intestines in our intestines that we don't want to harm. Phages are like guided missiles that only attack what they're supposed to." Because antibiotics kill lots of our own beneficial bacteria, our body would take a lot of time to recover from that. Also, because antibiotics kill bacteria, it leads to chaos, and other pathogens which could take advantage of the chaos could infect our body, leading to lots of confusion and inflicting more stress on our immune system, the system that protects our body from infections from other microorganisms.
Although phages have no direct impact on the human body other than getting rid of specific bacteria, they do have a few indirect effects that can be avoided if proper steps are taken to make sure there is nothing wrong with the phage. First and foremost, to understand the indirect effects of phages, one must understand the two pathways all viruses will chose from. The two main pathways all viruses, including phages, will take are the lytic cycle and the lysogenic cycle. In a nutshell, the lytic cycle is when the virus 'hijacks' the bacteria to make more copies of itself, and because there are too many viruses in the host cell, the cell will burst and die (Steward, 2024). Examples of this pathway are the flu virus and the smallpox virus. The other cycle, called the lysogenic cycle, is a cycle where the virus injects its genetic material (like RNA or DNA) into the host cell, so that it gets incorporated into the host cell's DNA. The virus will not be around, but the genetic material that is now a part of the host's DNA will be forever in the cell, and whenever the host cell replicates, the virus's genetic material will be passed on too. Then, when the host is in a stressful situation (like if there are no nutrients in the environment), the genetic material that was part of the host's DNA will activate, and new viruses will be made, killing the cell. But, if the virus's genetic material had a purpose other than creating more viruses, it could be bad for the organisms in the environment. For example, Dr. Sekse, a Norwegian veterinarian who works with pathogenic bacteria almost on a day-to-day basis, evidently informs, "A sequence of favorable circumstances needs to exist before E. Coli can produce disease. The most important of these is the ability to produce Shiga toxin. The gene that codes for Shiga toxin is not innate, but is contained within the bacteriophages. In other words, the bacterium needs first to be infected by a bacteriophage coding for Shiga toxin in order to produce the toxin itself." What Dr. Sekse is essentially suggesting is that the bacteria E. Coli, a regularly occurring bacteria in our intestines that aids in absorbing nutrients, becomes dangerous when a bacteriophage carrying the genetic material (DNA) that will allow for the bacteria to produce the Shiga toxin, a toxin that can damage our liver. But, there is something that solves this: we must use lytic viruses so that they will easily kill the bacteria quickly. Another common misconception that people often inaccurately over-exaggerate is that the bacteria will gain resistance to the bacteriophage. But, author Alexander Sulakvelidze understandably states, "Bacterial resistance to phages will unquestionably develop, although according to some authors, the rate of developing resistance to phages is approximately 10-fold lower than that of antibiotics." He also explains a solution to combat this resistance, clarifying, "[Resistance] can be partially circumvented by using several phages in one preparation..." Also, he analyzes, "it should be possible to select rapidly(in a few days or weeks) a new phage active against the phage-resistant bacteria."(2001) Sulakvelidze emphasizes that finding phages to combat resistant bacteria isn't very hard, especially when compared to finding new antibiotics. Also, since phages are also technically biological entities, they can also evolve to fight off bacteria, even when we do not interfere. This means that phages aren't as susceptible as antibiotics. An important fact to note is that as a bacterium gains more resistance to a phage, it will lose some resistance against the antibiotics. This eventually leads the bacteria into a trap, because we will have two modes of treating these bacteria, so we could switch treatments according to what the bacteria is more resistant to. Now that resistant bacterial infections are on the rise, phage therapy is becoming a more common occurrence for patients who are terminally ill, so they have no other hope of saving them from their plight. Because of this, more research and more funding for bacteriophages has skyrocketed, with some claims to use these viruses as the antibiotic itself. But the FDA's (U.S. Food and Drug Administration) process to approve drugs isn't compatible with phage therapy, because there are a multitude of phages that target different strains of bacteria, and testing and approving every single phage is a tedious and challenging work. So, in order for a better future to combat these antimicrobial bacteria, the FDA must fund more research and spread awareness for phage therapy, because it could very soon become our last hope if antibiotics fail us. Also, there isn't a lot of public awareness surrounding the multi-drug resistance epidemic, so there is obviously less advocacy surrounding phage therapy. The FDA is wrongly assuming that antibiotics work fine as it is, inaccurately portraying that the MDR epidemic isn't real. As progress has been made with the FDA's new approvals for phage therapy trials, the future looks to be promising, but if we want to solve the problem so that it doesn't emerge to become a global pandemic, the FDA needs to drastically increase the time, incentives, and effort put into phage trials, so that it can prove to be our savior when our attention will inevitably be turned to these multi-drug resistant beasts.
In essence, bacteriophage therapy must be accessible for not just terminally ill people, but also for those who have a medium severity infection, as they will immediately improve conditions of patients. But to consider this as a reality for humankind will be crazy as of now, because agencies like the FDA aren't trying to implement new phage testing sites fast enough. Although there has been progress, it is minimal, and to make our lives much easier and essentially make the world a much safer and
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